title: The heparin-binding domain of IGFBP-2 has insulin-like growth factor binding-independent biologic activity in the growing skeleton.
abstract: Insulin-like growth factor-binding protein 2 (IGFBP-2) is a member of a family of six highly conserved IGFBPs that are carriers for the insulin-like growth factors (IGFs). IGFBP-2 levels rise during rapid neonatal growth and at the time of peak bone acquisition. In contrast, Igfbp2(-/-) mice have low bone mass accompanied by reduced osteoblast numbers, low bone formation rates, and increased PTEN expression. In the current study, we postulated that IGFBP-2 increased bone mass partly through the activity of its heparin-binding domain (HBD). We synthesized a HBD peptide specific for IGFBP-2 and demonstrated in vitro that it rescued the mineralization phenotype of Igfbp2(-/-) bone marrow stromal cells and calvarial osteoblasts. Consistent with its cellular actions, the HBD peptide ex vivo stimulated metacarpal periosteal expansion. Furthermore, administration of HBD peptide to Igfbp2(-/-) mice increased osteoblast number, suppressed marrow adipogenesis, restored trabecular bone mass, and reduced bone resorption. Skeletal rescue in the Igfbp2(-/-) mice was characterized by reduced PTEN expression followed by enhanced Akt phosphorylation in response to IGF-I and increased β-catenin signaling through two mechanisms: 1) stimulation of its cytosolic accumulation and 2) increased phosphorylation of serine 552. We conclude that the HBD peptide of IGFBP-2 has anabolic activity by activating IGF-I/Akt and β-catenin signaling pathways. These data support a growing body of evidence that IGFBP-2 is not just a transport protein but rather that it functions coordinately with IGF-I to stimulate growth and skeletal acquisition.
authors.affiliation: Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, Maine 04074, USA.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kawai
authors.forename: Anne C
authors.initials: AC
authors.lastname: Breggia
authors.forename: Victoria E
authors.initials: VE
authors.lastname: DeMambro
authors.forename: Xinchun
authors.initials: X
authors.lastname: Shen
authors.forename: Ernesto
authors.initials: E
authors.lastname: Canalis
authors.forename: Mary L
authors.initials: ML
authors.lastname: Bouxsein
authors.forename: Wesley G
authors.initials: WG
authors.lastname: Beamer
authors.forename: David R
authors.initials: DR
authors.lastname: Clemmons
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Rosen
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D005260:Female; D006493:Heparin / Q000737:chemistry*; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018971:Insulin-Like Growth Factor Binding Protein 2; D051153:Wnt Proteins; D051176:beta Catenin; D006493:Heparin; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase